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cdk9 inhibitor and preparation method and application thereof

A technology of inhibitors and drugs, applied in the field of pharmaceutical compositions, CDK9 inhibitors and their preparation, can solve the problems of poor effect and obvious toxic and side effects, and achieve the advantages of strong effect, small toxic and side effects, and reduced production costs. Effect

Active Publication Date: 2022-08-09
SHENZHEN BAY LAB PINGSHAN TRANSLATIONAL MEDICINE CENT +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of this application is to provide a CDK9 inhibitor and its preparation method, as well as a pharmaceutical composition; to solve the problem of obvious toxic side effects and poor effect of CDK9 non-selective inhibitors in the prior art

Method used

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  • cdk9 inhibitor and preparation method and application thereof
  • cdk9 inhibitor and preparation method and application thereof
  • cdk9 inhibitor and preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0083] A second aspect of the embodiments of the present application provides a method for preparing a CDK9 inhibitor, comprising the following steps:

[0084]

[0085] The preparation method of the CDK9 inhibitor provided by the second aspect of the present application, the preparation method realizes the preparation of the CDK9 inhibitor through substitution reaction, catalytic cyclization / oxidation reaction, condensation or cyclization reaction, amination or alkylation reaction, and the reaction In the process, the raw materials are easily obtained, the reaction process is simple and easy to operate, the forward reaction rate is high, and the utilization rate of substrate atoms is high, which significantly improves the production efficiency and reduces the production cost.

[0086] The starting materials used in the preparation of the compounds of the present invention are known, or can be prepared according to known methods, or are commercially available. The intermedia...

Embodiment 1

[0107] Preparation of compound P3-01

[0108] Step a: Add 5-bromo-2,4-dichloropyrimidine (1.0eq), ethyl acetate (0.3M), DIPEA (2.0eq) and cyclopentylamine (1.5eq) to the reaction flask with magnetron ), and then reacted at room temperature for 6 hours. After the reaction, water was added to the system, extracted with ethyl acetate for three times, the organic phase was collected, dried and concentrated, and then purified by silica gel column chromatography. The mobile phase was n-hexane / ethyl acetate=9:1, The product S1 was isolated.

[0109]

[0110] Step b: S1 (1.0eq), cuprous chloride (0.1eq), potassium carbonate (3.0eq), sodium iodide (1.0eq) and 6-methyl-2 were added in sequence to the reaction flask equipped with magnetrons - Picolinic acid (0.3eq), the air in the bottle was replaced by argon with a double row tube, then anhydrous DMSO (0.2M) was added, followed by 3,3-diethoxyprop-1-yne ( 2.0eq). After the addition was completed, the reaction was heated to 115°C ...

Embodiment 2

[0120] Preparation of compound P3-14

[0121] Step g: 1) S3 (1.0 eq) and HBTU (1.1 eq) were added to the reaction flask equipped with the magnetron. The air in the bottle was replaced by argon with a double row tube, then anhydrous DMF (0.5M) was added, DIPEA (2.3eq) and dimethylhydroxylamine hydrochloride (1.1eq) were added by syringe, and the reaction was stirred at room temperature. After the reaction was monitored by TLC, water was added to the system, extracted three times with ethyl acetate, the organic phase was collected, dried and concentrated, and then purified by silica gel column chromatography. The mobile phase was n-hexane / ethyl acetate, and the product was isolated and obtained ; 2) After concentrating and drying the product (1.0eq) of step g 1), a magnetron was added to the reaction flask. The air in the bottle was replaced with argon using a double row tube, followed by addition of anhydrous THF (0.3M). The reaction flask was placed in an ice-water bath at 0...

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Abstract

The present application provides a CDK9 inhibitor, the CDK9 inhibitor is a pyrimidopyrrole kinase inhibitor, and the general chemical structure is shown in formula I: the CDK9 inhibitor is a pyrimidopyrrole kinase inhibitor, the pyrimidopyrrole kinase inhibitor The protein target to which the kinase is adapted is the serine / threonine kinase CDK9, and this CDK9 inhibitor exhibits high specificity and low cytotoxicity, providing an anti-CDK9 inhibitor for the prevention or treatment of tumor growth and metastasis. It is a selective CDK9 inhibitor with less toxic and side effects and strong effect, so that the biological function of CDK9 can be regulated by the inhibitor, and the growth and proliferation of tumors can be inhibited.

Description

technical field [0001] The application belongs to the technical field of medicinal chemistry, and in particular relates to a CDK9 inhibitor, a preparation method thereof, and a pharmaceutical composition. Background technique [0002] At present, the incidence of cancer is increasing, and about 4.2 million people die of cancer every year in the world. Cancer cases in China accounted for nearly half of the world in 2012, ranking first. Drugs for the treatment of cancer mainly include cytotoxic drugs and molecular target drugs. Cytotoxic drugs, namely traditional chemotherapy drugs, mainly inhibit tumor growth by killing rapidly dividing tumor cells. However, cytotoxic drugs can also harm cells that divide rapidly under normal conditions, such as bone marrow, gastrointestinal tract and hair follicle cells, etc., resulting in common side effects in chemotherapy: bone marrow suppression, mucositis, hair loss, etc. Targeted drug therapy works by interfering with specific prote...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/675A61P35/00A61P35/02
CPCC07D487/04A61P35/00A61P35/02
Inventor 黄湧蒋晨然余慧东陈杰安杨敬垒侯廷军潘培辰
Owner SHENZHEN BAY LAB PINGSHAN TRANSLATIONAL MEDICINE CENT
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